Production of alpha-nitroketones



United States Patent roe 3,040,1t

3,040,100 PRODUCTION OF ALPHA-NITROKETONES Gustave B. Baclnnan,Lafayette, Ind, and Takeo Hokama, Pittsburgh, Pa., assignors to PurdueResearch Foundation, West Lafayette, 11111., a corporation of Indiana NoDrawing. Filed May 8, 1959, Ser. No. 811,800

8 Claims. (Cl. 260-592) Our invention relates to the production ofalpha-nitroketones. More particularly, it relates to the production ofalpha-nitroketones by the C-acylation of primary nitroalkanes with acylcyanides under basic conditions.

Although alpha-nitroketones were first prepared in 1898, the chemicalproperties of these compounds have not been investigated to any greatextent, largely because of the difficulty in preparing these compounds.Most of the various methods which have been suggested in the literaturefor the production of alpha-nitroketones do not represent even goodlaboratory methods because of the low yields, complexity of reactionsequences, difiiculty of separation procedures and limitations tospecific functional groupings.

We have now discovered a method for the production of alpha-nitroketoneswhich not only gives greatly improved yields of the desired compounds,but at the same time is free from most of the objectional features ofthe prior processes suggested for the preparation of these compounds.Our new process consists essentially of accomplishing the C-acylation ofprimary nitroalkanes with acyl cyanides under basic conditions whereby30-70% yields of alpha-nitroketones are obtained. Our improved resultsare accomplished by effecting the acylation of a primary nitroalkane inthe salt form using an acyl cyanide, the reaction being carried outunder basic conditions and preferably in a suitable solvent.

Our process is applicable generally to the C-acylation of primarynitroalkanes; examples of which include nitromethane, nitroethane,l-nuitropropane, l-nitrobutane, lnitrooctane, and so forth.

We have found that the particular salt of the primary nitroallrane usedaifects to a considerable degree the yield of C-acylation product. Theexact reason for these variations is not known, but it is believed thatthey probably result from the different solubilities of the differentprimary nitroalkane salts. The lithium salts of the primarynitroalkanes, for example, were found to give higher yields than thecorresponding sodium salts. The lithium salts are al o easier to preparethan the corresponding sodium salts. in general, the more soluble thesalt, the more highly reactive it is under our acylation conditions. Wecan, therefore, carry out our acylation process with any stable solublemetal salt of a primary nitroalkane. Tne silver salts, for example, areunstable and hence of little utility. The mercury salts are relativelyinsoluble and hence not reactive. We have found the alkali metal saltsof the primary nitroalkanes to be the most satisfactory in our process.

As the acylating agent we can use acyl cyanides including alkanoylcyanides such as acetyl cyanide, propionyl cyanide, butyryl cyanide andaroyl cyanides such as benzoyl cyanide.

Our acylation process is preferably carried out in a suitable solventmedium which must be a solvent for the nitroalkane salt, the acylcyanide, and should be inert to both of these materials as well as theresulting acylated reaction products. The nitroalkane salts have limitedsolubilities in most organic solvents. One of the better types ofsolvent for these salts are tertiary aliphatic alcohols such as tertiarybutanol. In ethanol and Z-propanol, for example, the reaction of thesolvent with the acyl cyanide predominates and esters are the principalproducts.

'65-67 C., mixture.

Patented June 19, 1962 Other suitable solvents include tetrahydrofuran,pyridine, ether, etc. Solvents which do not contain active hydrogens areordinarily satisfactory for our process.

The acylation process can be carried out at temperatures ranging from0-75 C. Ordinarily, the reaction can be satisfactorily effected at roomtemperature.

Our invention will be illustrated by the following specific examples. Itshould be understood, however, that we are not limited either to thespecific amounts or ratios of added ingredients shown therein nor thespecific method of mixing the reactants. It is understood that the usualvariations and procedures obvious to one skilled in the art are includedwithin the scope of our invention.

Example I Nitromethane, 12.2 g. (0.2 mole), was added during a period of15 minutes to a solution of sodium ethoxide formed by reacting sodiummetal, 4.6 g. (0.2 mole), with ethanol (300 ml.) in a 500 ml., 3-neckedflask equipped with a stirrer, dropping funnel and reflux condenserprotected with a sodium hydroxide drying tube. Benzoyl cyanide, 26 g.(0.2 mole), was added during a period of 30 minutes to the cooledsuspension and a mixture was stirred for four hours. The suspension wasfiltered and the precipitated was washed with dry ether ml.). The solidwas partially dissolved in water (200 ml.) and acidified with dilutehydrochloric acid (3 N, 200 ml.) at 0.5 C. The suspension was filteredand the solid was dried and recrystallized from an ether-petroleumether, B.P. Yield of nitroacetophenone, 3 g. (9% theory), M.P. -406 C.

Example 11 Sodium t-butoxide was formed by reacting sodium metal, 2.3 g.(0.1 mole), with t-butanol (dried over calcium hydride), 300 ml., at areflux temperature for 12-14 hours. l-nitropropane, 18 g. (0.2 mole),was added during a period of 20 minutes to the cooled suspension and themixture was stirred for 30 minutes. Benzoyl cyanide, 13 g. (0.1 mole),was added to the suspension during a period of 30 minutes and thereaction mixture was stirred at room temperature for 5 hours. After themajor portion of the solvent was removed under a water aspirator, theresidue was taken up in a mixture of benzene (100 ml.), and Water (200ml.) and acidified with 10% acetic acid solution (100 ml.). The benzenelayer was separated and the aqueous solutionwas extracted three timeswith benzene (50 ml. portions). The combined benzene solutions werewashed with water and dried over magnesium sulfate. Distillation gavebenzoic acid, 4.0 g. and alphanitrobutyrophenone, 5.0 g. (2.6% theory),RP. 1l51l8 C. (1 mm.), n 1.5326.

Example III Lithium t-butoxide was formed by dissolving lithium metal,0.7 g. (0.1 mole), in dry t-butanol (300 ml.) by heating the alcoholsolution to a gentle reflux for two hours. l-nitropropane, 18 g. (0.2mole), was added during a period of 15 minutes to the cooled solutionand the resulting mixture was stirred for 15 minutes. Benzoyl cyanide,13 g. (0.1 mole), was added during a period of 30 minutes to thesuspension and the mixture was stirred for four hours at roomtemperature. .After the major portion of the solvent was removed underwater aspiration, the residue was taken up in a mixture of ether (200ml.) and water (200 ml.) and acidified with 10% acetic acid solution(100 ml.) containing urea, 10 g. The aqueous layer was extracted fivetimes with ether (50 ml. portions) and the combined ether solutions werewashed with Water and dried over magnesium sulfate. Distillation gavealpha-nitrobutyrophenone, 12 g. (62% theory), 13.1. 114 C. (1 mm.), n1.5334.

3 Analysis.-Calculated for C H -NO C, 62.16; H, 5.74; N, 7.25. Found: C,62.17; H, 6.00; N, 7.49.

Example I V Using the above procedure, benzoyl cyanide, 22 g. (0.1 mole)was reacted with lithium ethanenitronate, 16 .4 g. (0.2 mole), int-butanol, 400 ml., for five hours at room temperature.Alpha-nitropropiophenone, 15 g. (50% theory), B.P. 124 C. (1-2 mm.), n1.5434 was isolated on distillation.

Analysis.Calculated for C H NO C, 60.33; H, 5.06; N, 7.82. Found: C,60.28; H, 5.40; N, 8.12.

Example V Benzoyl cyanide, 13 g. (0.1 mole), was reacted with lithiuml-butanenitronate, 21.4 g. (0.2 mole), in dry t-butano1, 400 ml.,according to the procedure outlined in Example III with lithiuml-propanenitronate. After six hours at room temperature, the reactionmixture was concentrated, taken up in a mixture of ether, 100 ml., andwater, 400 ml., and acidified with acetic acid solution, 200 ml.,containing urea, 10 g. The ether layer was separated, and the aqueouslayer was extracted three times with ether (50 ml. portions). The ethersolution was washed with Water, and dried over magnesium sulfate. Thedried ether solution was chilled in a Dry Ice bath andalpha-nitrovalerophenone, 2.5 g. was precipitated and filtered. Thisoperation Was repeated several times with the mother liquor, and anadditional 8.5 g. of solid was isolated and recrystallized frompetroleum ether (B.P. 35-60 C.). A total of 11 g. (53% theory), ofalpha-nitrovalerophenone, M.P. 48 C. was obtained.

Analysis.Calculated for C H NO C, 63.75; H, 6.32, N, 6.76. Found: C,63.56; H, 6.06; N, 6.75.

Example VI Benzoyl cyanide, 10 g. (0.077 mole), Was added during aperiod of 30 minutes to a suspension of lithium 1- propanenitronate, 9.5g. (0.1 mole), in dry pyridine (200 m1), and the reaction mixture wasstirred for a total of 8 hours at room temperature. The major portion ofthe solvent was removed under Water aspiration and the residue was takenup in a mixture of ether (100 ml.) and Water (200 ml.). The reactionmixture was acidified with 10% acetic acid solution (100 ml.) containingurea, 10 g., and the ether layer was separated. The aqueous layer wasextracted three times with ether (50 ml. portions). The combined etherextracts were Washed with water and dried over magnesium sulfate. Theether solution was concentrated, and the residual oil was distilledthrough a short Vigreaux column under nitrogen at reduced pressure.Alpha-nitrobutyrophenone, 8 g. (54% theory), B.P. 128 C. (1-2 mm.), 111.5336, was obtained.

Example VII Following the same procedure outlined in Example VI, benzoylcyanide, 10 g. (0.077 mole),was reacted with lithium l-propanenitronate,9.5 g. (0.1 mole), in tetrahydrofuran (200 ml.) at room temperature forfour hours and at 65 C. for one hour. Alpha-nitrobutyrophenone, 9 g.(60% theory) was isolated.

Example VIII The procedure described in Example VI was used for thereaction of benzoyl cyanide, 10 g. 0.077 mole), with lithiuml-propanenitronate, 9.5 g. (0.1 mole), in ether (200 ml.) at roomtemperature for 12 hours and at 35 C. for four hours.Alpha-nitrobutyrophenone, 1.9 g. (10% theory) was isolated.

Example IX Benzoyl cyanide, 13 g. (0.1 mole), was added during a periodof 0.5 hour to a mixture of nitromethane, 12 g. (0.2 mole), and sodiumcarbonate, 21 g. (anhydrous powder, 0.2 mole) in pyridine, 300 ml.(dried over calcium hydride),'and the reaction mixture was stirred for 43.5 hours. The suspension was filtered and the precipitate was washedwith dry ether (100 ml.). The solid was partially dissolved in water(400 ml.) and acidified with dilute hydrochloric acid (3 N, 200 ml.) at0-5 C. Nitroacetophenone, M.P. IDS-106 C., 12 g. (73% theory) wasisolated by filtration and recrystallization from ether-petroleum ether.

Analysis.Calculated for C H NO C, 58.18; H, 4.27; N, 8.48. Found: C,58.20; H, 4.37; N, 8.52.

Example X Nitroethane, 30 g. (0.4 mole), was added during the period of30 minutes to a cooled suspension of lithium t-butoxide prepared byreacting lithium metal, 1.7 g. (0.25 mole), with t-butanol (400 ml.),and the resulting mixture was stirred for a period of 30 minutes.Freshly distilled acetyl cyanide, 17 g. (0.25 mole), was added during aperiod of two hours to the suspension, and the mixture was stirred fortwo hours. After a major portion of the solvent was removed under wateraspiration, the residue was taken up in a mixture of water, 200 ml., andether, 100 ml., and acidified with 10% acetic acid solution (200 ml.)containing urea (10 g.). The aqueous solution was extracted five timeswith ether 100 ml. portions), and the combined ether solutions; werewashed with water and dried. The ether solution was concentrated and theresidue was flash distilled in vacuo under nitrogen. Yield, 30 g., B.P.2090 C. (1 mm). The crude product was fractionated through a two footspiral column and pure 3-nitro-2-butanone, 11.6 g. (30% theory), B.P. 58C. (1 mm), M 1.4362 was isolated.

Example XI The procedure described in Example X above was applied to thereaction of acetyl cyanide, 14 g. (0.2 mole), with lithiuml-propanenitronate, 16.2 g. (0.2 mole), in t-butanol (400 1111.).3-nitro-2-pentanone, 9.5 g. (36% theory), B.P. 52 C. (1 mm.), 12 1.4334,was isolated.

Analysis-Calculated for C I-I NO C, 45.79; H, 6.92; N, 10.68. Found: C,46.00; H, 7.15; N, 10.94.

Example XII The procedure described in Example X above was applied tothe reaction of acetyl cyanide, 14 g. (0.2 mole), with lithiuml-butanenitronate, 21.4 g. (0.2 mole), in tbutanol (400 ml). Slightlyimpure 3-nitro-2-hexanone, 11 g. (38% theory) B.P. 60 C. (1 mm.), n1.4372 was isolated.

Analysis.-Calculated for C H NO C, 49.64; H, 7.64; N, 9.65. Found: C,50.68; H, 8.59; N, 10.48.

Now having described our invention what We claim is:

1. A process for the production of alpha-nitroketones which comprisesreacting at temperatures ranging from 0 to C., an acyl cyanide selectedfrom the group consisting of alkanoyl cyanides and aroyl cyanides and analkali metal salt of a primary nitroalkane dissolved in a tertiaryaliphatic alcohol solvent medium for the nitroalltane salt, said solventmedium being substantially inert to the acyl cyanide, acidifying thethus produced reaction mixture and recovering the alpha-nitroketonethereby produced.

2. The process of claim 1 wherein the alkali metal salt of the primarynitroalkane is selected from the group consisting of the sodium salt andthe lithium salt of a nitroalkane.

3. The process of claim 1 wherein the primary nitroalkane is selectedfrom the group consisting of nitromethane, nitroethane, l-nitropropane,and l-nitrobutane.

4. The process of claim 1 wherein the inert solvent is t-butanol.

5. A process for the production of alpha-nitroketones which comprisesreacting at temperatures ranging from 0 to 75 C., an akanoyl cyanide andan alkali metal salt of a primary nitroalkane dissolved in a tertiaryaliphatic alcohol solvent medium for the said salt of the 5 primarynitroalkane, said solvent medium being substantially inert to thealkanoyl cyanide, acidifying the thus produced reaction mixture andrecovering the alpha-nitroketone thereby produced.

6. The process of claim 5 wherein the alkanoyl cyanide is acetyl cyanideand the primary nitroalkane is selected from the group consisting ofnitromethane, nitroethane, l-nitropropane, and l-nitrobutane.

7. A process for the production of alpha-nitroketones which comprisesreacting at temperatures ranging from 0 to 75 C., an aroyl cyanide andan alkali metal salt of a primary nitroalkane dissolved in a tertiaryaliphatic alcohol solvent medium for the said salt of the primarynitroalkane, said solvent medium being substantially inert to the aroylcyanide, acidifying the thus produced reaction mixture and recoveringthe alpha-nitroketone thereby produced.

6 8. The process of claim 7 wherein the aroyl cyanide is benzoyl cyanideand the primary nitroalkane is selected from the group consisting ofnitromethane, nitroethane, l-nitropropane, and l-nitrobutane.

References Cited in the file or" this patent UNITED STATES PATENTS2,286,795 Dickey et al June 16, 1942 OTHER REFERENCES Hackhs ChemicalDictionary (3rd edition), page 18 (1944).

Fieser et 211.: Organic Chemistry (2nd edition), pages 231-2 (1950).(Copies of above in Library.)

1. A PROCESS FOR THE PRODUCTION OF ALPHA-NIRTOKETONES WHICH COMPRISESREACTING AT TEMPERATURES RANGING FROM 0 TO 75*C., AN ACYL CYANIDESELECTED FROM THE GROUP CONSISTING OF ALKANOL CYANIDES AND AROYLCYANIDES AND AN ALKALI METAL SALT OF A PRIMARY NITROALKANE DISSOLVED INA TERTIARY ALIPHATIC ALCOHOL SOLVENT MEDIUM FOR THE NITROALKANE SALT,SAID SOLVENT MEDIUM BEING SUBSTANTIALLY INERT TO THE ACYL CYANIDE,ACIDIFYING THE THUS PRODUCED REACTION MIXTURE AND RECOVERING THEAPLHA-NOITROKETOINE THEREBY PRODUCED.